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Background Patients with persistent fever and neutropenia often receive empirical therapy with conventional or liposomal amphotericin B for the prevention and early treatment of invasive fungal infections. Caspofungin, a member of the new echinocandin class of compounds, may be an effective alternative that is better tolerated than amphotericin B.
Methods In this randomized, double-blind, multinational trial, we assessed the efficacy and safety of caspofungin as compared with liposomal amphotericin B as empirical antifungal therapy. At study entry, patients were stratified according to risk and according to whether they had previously received antifungal prophylaxis. A successful outcome was defined as the fulfillment of all components of a five-part composite end point.
Results Efficacy was evaluated in 1095 patients (556 receiving caspofungin and 539 receiving liposomal amphotericin B). After adjustment for strata, the overall success rates were 33.9 percent for caspofungin and 33.7 percent for liposomal amphotericin B (95.2 percent confidence interval for the difference, –5.6 to 6.0 percent), fulfilling statistical criteria for the noninferiority of caspofungin. Among patients with baseline fungal infections, a higher proportion of those treated with caspofungin had a successful outcome (51.9 percent vs. 25.9 percent, P=0.04). The proportion of patients who survived at least seven days after therapy was greater in the caspofungin group (92.6 percent vs. 89.2 percent, P=0.05). Premature study discontinuation occurred less often in the caspofungin group than in the amphotericin B group (10.3 percent vs. 14.5 percent, P=0.03). The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in the two groups. Fewer patients who received caspofungin sustained a nephrotoxic effect (2.6 percent vs. 11.5 percent, P<0.001), an infusion-related event (35.1 percent vs. 51.6 percent, P<0.001), or a drug-related adverse event or discontinued therapy because of drug-related adverse events.
Conclusions Caspofungin is as effective as and generally better tolerated than liposomal amphotericin B when given as empirical antifungal therapy in patients with persistent fever and neutropenia.
Amphotericin B and its lipid formulations, as well as triazoles (fluconazole, itraconazole, and voriconazole), have been studied as empirical antifungal agents in patients with persistent fever and neutropenia.4,5,6,7,8,9,10,11 However, these agents may be associated with toxicity and adverse drug interactions and have a limited spectrum of activity, erratic bioavailability, unpredictable pharmacokinetics, and limited efficacy. There is therefore a critical need for new classes of antifungal agents for use as empirical therapy in patients with persistent fever and neutropenia.
Echinocandins are a relatively new class of antifungal agents that noncompetitively inhibit the synthesis of fungal cell-wall 1,3-
-D-glucan. Caspofungin has activity against candida species and aspergillus species12,13,14,15,16 and has been approved for the primary treatment of esophageal candidiasis, candidemia, and other candida infections (intraabdominal abscesses, peritonitis, and pleural-space infections) and for the treatment of invasive aspergillosis that is refractory to or intolerant of other antifungal therapy.17,18,19,20,21 We therefore investigated the efficacy and safety of caspofungin as compared with those of liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia.
Methods
Study Design
This was a prospective, double-blind study conducted from January 2000 through August 2002 at 116 sites in 26 countries. Written informed consent was obtained from all the patients, and all the institutional review boards approved of the protocol and consent form. No modifications to the protocol procedures were made during the course of the study.
Randomization
After persistent fever and neutropenia had been documented, patients who fulfilled all the other enrollment criteria were eligible for randomization. Randomization in a 1:1 ratio was performed at each site with the use of a blocking factor of four. Before randomization, patients were stratified according to two variables: risk (high or low) and use of systemic antifungal prophylaxis (yes or no). High-risk patients were those who had undergone allogeneic stem-cell transplantation or who had relapsed acute leukemia; low-risk patients were all others. Separate random-assignment schedules were used for high-risk and low-risk patients; for patients who had used systemic antifungal prophylaxis and those who had not, the lowest and highest random-assignment numbers available, respectively, on the appropriate assignment schedules were used.
Data and Safety Monitoring Board and Adjudication Committee
When the study began, an independent data and safety monitoring board and adjudication committee were appointed. The data and safety monitoring board, composed of clinicians and a statistician not connected with the study, monitored all the blinded safety data and, at a prespecified time, reviewed the unblinded efficacy and safety data to determine whether the study should continue. No changes to the study were made on the basis of this review.
The adjudication committee, composed of two of the authors and one specialist in infectious diseases, all of whom had extensive experience in the treatment of fungal infections, reviewed the blinded data and classified all suspected fungal infections (as proven, probable, or possible infections or as not fungal infections) on the basis of prespecified consensus criteria defined by the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycoses Study Group.22 The adjudication committee members also determined the causal pathogen, time of onset of infection, and response of baseline infections to study treatment, according to a prespecified protocol. Baseline infections were those present on or before day 2 of the study, and breakthrough infections those with an onset on day 3 or later. The assessments of the adjudication committee were final, and only fungal infections that the committee judged to be probable or proven were considered documented infections for the purpose of study analysis.
Blinding
Blinding was rigorously conducted by means of a double-blind, double-dummy procedure. Opaque covers were used to conceal the infusion bags and catheters used for infusions of liposomal amphotericin B and the corresponding placebo. The placebo infusions were color-matched to the corresponding active-drug infusions; for the placebo corresponding to liposomal amphotericin B, a multivitamin solution was added to 5 percent dextrose to create a yellow solution, and for the placebo corresponding to caspofungin, normal saline was used.
Patients
Male and female patients 16 years of age or older were eligible to participate if they had received chemotherapy for cancer or had undergone hematopoietic stem-cell transplantation and if they had had an absolute neutrophil count below 500 per cubic millimeter for at least 96 hours, had fever (a temperature above 38.0°C), and had received parenteral antibacterial therapy for at least 96 hours. Patients were not eligible if they had an inadequately managed bacterial infection, documented invasive fungal infection, or a Karnofsky score below 30 (on a scale from 0 to 100, where lower scores indicate worse function) at the time of enrollment. Other exclusion criteria were a history of serious allergy to the study drugs, a bilirubin or alkaline phosphatase level more than three times the upper limit of normal, an aspartate or alanine aminotransferase level more than five times the upper limit of normal, a platelet count below 5000 per cubic millimeter, and a requirement for rifampin, cyclosporine, or concomitant systemic antifungal therapy.
Study Therapy
Patients were assigned to receive either intravenous caspofungin (70 mg on day 1 and 50 mg once daily thereafter) plus placebo corresponding to liposomal amphotericin B or liposomal amphotericin B (3.0 mg per kilogram of body weight daily) plus placebo corresponding to caspofungin. Premedication was not allowed on day 1, but if an infusion-related reaction occurred, its administration was subsequently allowed. If the study therapy was well tolerated but fever persisted for five or more days and the patient's clinical condition deteriorated, the dosage could be increased (to 70 mg once daily in the case of caspofungin and to 5.0 mg per kilogram per day in the case of liposomal amphotericin B). For patients who did not have evidence of baseline or breakthrough fungal infection, study therapy was administered until the absolute neutrophil count was at least 500 per cubic millimeter and for up to 72 hours thereafter. The on-site investigator determined the duration of therapy for patients with baseline or breakthrough fungal infections; however, it was recommended that treatment be given for at least 14 days and for at least 7 days after neutropenia and symptoms resolved.
Analysis
The population in whom the primary efficacy analysis was conducted was a modified intention-to-treat population, comprising patients with persistent fever and neutropenia who had been randomly assigned to a study group and who had received at least one complete dose of study medication. Safety and tolerability were assessed in all patients who received at least one dose of active study drug.
Efficacy Assessments
The primary efficacy end point was a favorable overall response, as determined by a five-component end point that has been used in previous studies of empirical antifungal therapy.4,5,7,8 Treatment was considered successful if all five of the following criteria were met: successful treatment of any baseline fungal infection, absence of any breakthrough fungal infection during therapy or within seven days after the completion of therapy, survival for seven days after the completion of therapy, no premature discontinuation of study therapy because of drug-related toxicity or lack of efficacy, and resolution of fever (defined as a temperature below 38°C for at least 48 hours) during neutropenia. Secondary efficacy assessments consisted of assessments of each component of the primary end point. Survival times were also assessed for the modified intention-to-treat population.
Safety Assessments
Investigators monitored patients for clinical adverse events daily during the administration of the study therapy and for 14 days thereafter and assessed whether any adverse event was related to the study therapy. Infusion-related events (systemic symptoms during and one hour after infusion) were prospectively defined, evaluated daily, and reported as adverse events. Laboratory studies were performed at the time of enrollment, twice weekly during therapy, at the end of therapy, and two weeks after the end of therapy.
Role of Sponsor
This study was designed by three of the authors (Drs. Walsh and dePauw, in collaboration with Dr. Sable). It was modeled after a previous double-blind trial, the National Institute of Allergy and Infectious Diseases Mycoses Study Group study 32.5 Two of the authors were involved at all levels in the design, implementation, and analysis phases of the study. Data were collected and analyzed initially by the sponsor. All data in the study were source-documented. All the authors had full access to the primary data and to their analysis. There was full independence in decisions concerning the reporting of results and the content of the manuscript, with no interference from the sponsor.
Statistical Analysis
All the primary and secondary analyses presented here, including analyses of the components of the primary end point, were prespecified; no selectivity was used. The primary analysis was designed to show whether the outcome in the caspofungin group was noninferior to that in the liposomal amphotericin B group. According to the prespecified definition, noninferiority with respect to the primary efficacy end point would be demonstrated if the two-sided 95.2 percent confidence interval (calculated with use of the adjusted alpha value of 0.048, on the basis of the interim analysis conducted by the data safety and monitoring board) for the difference in response rates between the treatment groups (the rate with caspofungin minus the rate with liposomal amphotericin B) included 0 and the lower limit was not less than –10 percent (i.e., 10 percentage points in favor of liposomal amphotericin B). An adjustment for stratification was used.
For the overall and individual end points, the observed proportion of patients with a favorable outcome was determined and 95 percent confidence intervals were calculated with use of the normal approximation to the binomial distribution. The analysis plan designated the modified intention-to-treat population as the population for which the primary end point was determined. For the primary end point, the estimated proportion of patients with a favorable overall outcome in each group and its 95 percent confidence interval and the difference in response rates and its 95.2 percent confidence interval were calculated with use of the Cochran–Mantel–Haenszel adjustment for stratification.23 Assuming a 50 percent success rate in the liposomal amphotericin B group and a significance level of 4.8 percent, a sample of 530 patients per treatment group in the modified intention-to-treat analysis was chosen to demonstrate noninferiority with a power of 90 percent.
In the analysis of the survival end point in the modified intention-to-treat population, patients who were lost to follow-up within seven days after the completion of therapy were considered to have had treatment failure. Kaplan–Meier estimates of survival time were determined. Differences in survival times between the two treatment groups were assessed with a log-rank test at the 5 percent significance level.
The main safety analysis evaluated the proportion of patients with a baseline creatinine clearance above 30 ml per minute who had nephrotoxicity (a doubling of the serum creatinine level or, if the value was elevated at the time of enrollment, an increase of at least 1 mg per deciliter [88 µmol per liter]). In the analysis of nephrotoxicity, noninferiority was demonstrated if the lower limit of the 95 percent confidence interval for the difference in proportions between treatment groups (caspofungin minus liposomal amphotericin B) was 0 or less (where negative values favored caspofungin) and the upper limit was not greater than 5 percent. Infusion-related events, any drug-related adverse events, and drug-related adverse events leading to discontinuation were analyzed by testing the difference in proportions between groups. The most common specific drug-related adverse events were analyzed with the use of 95 percent confidence intervals for the difference in proportions between the treatment groups. All P values were two-sided and were not adjusted for multiple comparisons. P values 
0.05 were considered to indicate statistical significance.
Results
Patients
Of 1123 patients who underwent randomization, 1111 were treated and 1095 were included in the modified intention-to-treat population. Baseline demographic characteristics were balanced between the two treatment groups (Table 1). An underlying hematologic cancer was present in 94.2 percent of the patients, predominantly acute myelogenous leukemia. The duration of therapy was similar in the two treatment groups: the mean duration was 13.0 days (median, 11 [range, 1 to 90]) in the caspofungin group and 12.5 days (median, 10 [range, 1 to 90]) in the liposomal amphotericin B group.
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In the analysis of the primary end point, adjusted for strata, 33.9 percent of patients who received caspofungin and 33.7 percent of those who received liposomal amphotericin B had a favorable overall response (95.2 percent confidence interval for the difference between caspofungin and liposomal amphotericin B, –5.6 to 6.0 percent) (Table 2); thus, caspofungin fulfilled the statistical criteria for noninferiority to liposomal amphotericin B. Among high-risk patients in both treatment groups, observed overall response rates were somewhat higher than the rates in low-risk patients. Prior antifungal prophylaxis did not significantly affect overall response rates.
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Rates of each component of the primary end point are shown in Table 2 and Figure 1. The data suggest that caspofungin-treated patients had better outcomes than the patients treated with liposomal amphotericin B with respect to three of the components: survival for at least seven days after treatment, successful treatment of baseline fungal infection, and absence of premature study discontinuation. Baseline fungal infections were diagnosed in 27 patients in each group; the most common were aspergillus pneumonia and candidemia. Of the patients with baseline fungal infections, more of those treated with caspofungin than of those treated with amphotericin B had a successful outcome. This was true for both invasive candidiasis and aspergillosis. The rate of occurrence of breakthrough fungal infections was similar in the two treatment groups. Among these patients, 48 percent receiving caspofungin and 35 percent receiving liposomal amphotericin B were classified as being at high risk. The proportion of patients who survived for at least seven days after therapy was greater in the caspofungin group than in the amphotericin B group. Premature study discontinuation because of toxicity or lack of efficacy occurred more often in the amphotericin B group than in the caspofungin group. The difference between the treatment groups was greatest with respect to discontinuations because of toxicity.
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Safety and Tolerability
Significantly fewer patients in the caspofungin group than in the liposomal amphotericin B group had an event associated with nephrotoxicity, an infusion-related event, or any drug-related adverse event or discontinued therapy because of a drug-related adverse event (Table 3). Although the rates of drug-related adverse events reported most frequently were similar in the two groups, several of them — chills, nausea, vomiting, a decrease in the serum potassium level, an elevation in the serum alkaline phosphatase level, and an elevation in the serum creatinine level — occurred less often with caspofungin than with amphotericin B.
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Overall study mortality, including the rate of death after the seven-day survival end point, was 10.8 percent (61 patients) in the caspofungin group and 13.7 percent (75 patients) in the liposomal amphotericin B group. The Kaplan–Meier analysis (Figure 2) indicated that the proportion of patients who survived to the prespecified seven-day survival end point was greater in the caspofungin group than in the liposomal amphotericin B group (log-rank chi-square = 4.05, P=0.04). The causes of death were primarily complications of underlying diseases or infections and were distributed similarly in the two treatment groups. Among those who had a baseline fungal infection, the rate of death during the study was lower in the caspofungin group (11.1 percent [3 of 27 patients]) than in the amphotericin group (44.4 percent [12 of 27]); in contrast, among patients with breakthrough fungal infections, mortality was similar in the two groups (34.5 percent in the caspofungin group [10 of 29 patients died] and 41.7 percent in the liposomal amphotericin B group [10 of 24 died]).
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This comparative trial, conducted in more than 1100 patients with neutropenia, showed that caspofungin was a suitable alternative to liposomal amphotericin B as empirical therapy and offered the advantages of safety, improved survival, and improved response rates in patients with invasive fungal infections. Thus, this large, double-blind, randomized, multicenter trial showed that an echinocandin has efficacy as empirical antifungal therapy in patients with persistent fever and neutropenia. More than 100 centers participated, allowing the study population to reflect the broad population of patients in North America and Europe. In addition, the adjudication committee classified all invasive fungal infections according to the new international criteria,22 thus allowing worldwide interpretation of the data in adults. Patients younger than 16 years of age were not enrolled; because the plasma pharmacokinetics of caspofungin in children differ from those in adults, further evaluation in children is warranted.26
The study is distinct from previous studies of empirical antifungal therapy in demonstrating improvements in survival and in the outcomes of baseline fungal infections and in placing an emphasis on patients with acute leukemia.4,5,6,7,8 The high-risk nature of this study population is reflected by the designation of approximately 25 percent of the patients (more than 70 percent of whom had acute leukemia) as being at high risk and by the median duration of therapy of 10 to 11 days. Patients with breakthrough infections appeared to be a particularly high-risk group as compared with the overall study population. More of the patients who had breakthrough infections than of those in the modified intention-to-treat study population were classified as being at high risk.
The choice of dose of liposomal amphotericin B (3 mg per kilogram) was based on the dose of liposomal amphotericin B that has been approved by the Food and Drug Administration for empirical antifungal therapy in patients with persistent fever and neutropenia.5 This dose was also used for comparison with voriconazole and with lipid formulations of amphotericin B in other randomized trials.4,6
That caspofungin, an echinocandin, was associated with an overall response similar to that provided by a lipid formulation of amphotericin B represents an important benchmark in the understanding of comparative antifungal efficacy. Liposomal amphotericin B is better tolerated than conventional amphotericin B and is considered by many to be a more appropriate formulation for comparison. Nevertheless, caspofungin was similar in terms of overall success when assessed according to rigorously defined criteria. Moreover, the results of this study shed light on the properties of caspofungin. That caspofungin was active in treating baseline fungal infections (including pulmonary aspergillosis) and candidemia is a finding consistent with its efficacy in the primary treatment of candidemia and other deep-seated candidal infections and in salvage therapy for invasive aspergillosis in patients who do not have a response to amphotericin B.20,21 Experimental data also demonstrate the in vitro and in vivo activity of caspofungin against Candida albicans and many candida species other than C. albicans and in animal models of invasive aspergillosis.13,14,15,16 Caspofungin is fungicidal against actively growing cells of Aspergillus fumigatus.27 Patients with breakthrough infections appeared to be a particularly high-risk group as compared with the overall, modified intention-to-treat study population. The improved safety and tolerability profile of caspofungin also permitted more patients to continue to receive the study therapy. The increased rates of renal and infusion-related toxicity associated with liposomal amphotericin B may add an additional burden in patients whose condition is already compromised. Thus, the outcome associated with caspofungin may be related both to its antifungal efficacy and to its safety profile.
In summary, caspofungin was as efficacious as liposomal amphotericin B in patients with persistent fever and neutropenia and was, overall, better tolerated than liposomal amphotericin B. Thus, caspofungin provides a new option for empirical antifungal therapy in these patients.
Supported primarily by individual institutional grants from Merck.
Dr. Baden reports having received grant support from Merck; Dr. Cornely consultation or lecture fees or grant support from Fujisawa, Gilead Sciences, Merck Sharp & Dohme, Pfizer, and Schering-Plough Research Institute; Dr. dePauw consultation or lecture fees from Fujisawa, Gilead, Merck Sharp & Dohme, Pfizer, and Vicuron; Dr. Maertens consultation or lecture fees from Gilead, GlaxoSmithKline, Fujisawa, Merck, Pfizer, and Schering-Plough; Dr. Donowitz consultation fees from Schering-Plough and grant support from Enzon, Fujisawa, and Merck; and Dr. Walsh grant support from Fujisawa and Merck.
We are indebted to Gail L. Woods, M.D., and Jeniffer Rabb for assistance in the preparation of the manuscript.
Source Information
From the National Cancer Institute, National Institutes of Health, Bethesda, Md. (T.J.W.); Merck Research Laboratories, West Point, Pa. (H.T., M.R.B., R.J.L., C.A.S.); University of Virginia Health System, Charlottesville (G.R.D.); Universitaire Ziekenhuizen Leuven, Leuven, Belgium (J.A.M.); Brigham and Women's Hospital and Dana–Farber Cancer Institute — both in Boston (L.R.B.); Clinical Hospital No. 4, Lublin, Poland (A.D.); Klinikum der Universität zu Köln, Cologne, Germany (O.A.C.); and University Hospital St. Radboud, Nijmegen, the Netherlands (B.E.P.).
Address reprint requests to Dr. Walsh at the National Cancer Institute, Bldg. 10, Rm. 13N-240, 10 Center Dr., Bethesda, MD 20892.
References
In addition to the authors, the following investigators participated in the study: Argentina — J. Altclas (Sanatorio Mitre, Buenos Aires); Australia — J. Harkness (St. Vincent Hospital, Sydney), M. Slavin (Royal Melbourne Hospital and Victorian Infectious Diseases Services, Melbourne), J. Seymour (Peter MacCallum Cancer Institute, Melbourne); Austria — K. Lechner (Universitäts Klinik für Innere Medizin I, Vienna); Brazil — A. Anelli (Hospital do Câncer, Fundação Antonio Prudente, São Paulo), M. Nucci (Hospital Universitário, Universidade Federal de Rio de Janeiro, Rio de Janeiro); Canada — E. Bow (Health Science Center, Winnipeg, Man.), R. Feld (Princess Margaret Hospital, Toronto), M. Laverdiere (Hôpital Maisonneuve–Rosemont, Montreal), A. McCarthy (Ottawa Hospital, Ottawa, Ont.), C. Rotstein (McMaster Medical Unit Henderson General Hospital, Hamilton, Ont.), S. Sanche (Royal University Hospital, Saskatoon, Sask.); Chile — J. Alfaro (Hospital Clínico Universidad de Chile, Santiago); Colombia — O. Sussman (Clínica DeMarly, Bogota); Czech Republic — E. Drahokoupilova (Department of Pediatric Oncology, University Hospital Motol, Prague), K. Indrak (University Hospital Olomouc, Olomouc), V. Koza (Charles University Hospital, Plzen), J. Mayer (University Hospital Brno-Bohunice, Brno-Bohunice), J. Sterba (University Hospital Brno, Brno), M. Trneny (General Faculty Hospital, 1st Clinical Department of Internal Medicine, Prague); France — J.P. Marie (Hôpital de I'Hôtel-Dieu de Paris, Service d'Hématologie Clinique 1, Paris), J.P. Vernant (Hôpital Pitié-Salpêtrière Service d'Hématologie Clinique, Paris), J.H. Bourhis (Institut Gustave Roussy Département de Médecine, Villejuif); Germany — H.-A. Horst (II Medizinische Klinik der Christian-Albrechts Universität, Kiel), A. Glasmacher (Rheinische Friedrich-Wilhelms-Universität, Medizinische Klinik, Bonn), M. Ruhnke (Charité, Campus Virchow Klinikum, Berlin), H.-J. Illiger (Städtische Kliniken Oldenburg, Klinik für Innere Medizin II, Oldenburg), G. Höffken (Medizinische Fakultät Carl Gustav Carus der Technischen Universität Dresden, Dresden), H. Bertz (Universitätsklinikum Freiburg, Medizin I, Freiburg), G. Fätkenheuer (Universitätsklinik Köln, Klinik I für Innere Medizin, Cologne), W. Kern (Universitätsklinikum Ulm, Innere Medizin II, Ulm), G. Maschmeyer (Universitätsklinikum Charité, Robert Rössle Klinik, Berlin), H. Einsele (Universitätsklinikum Tübingen, Medizinische Klinik, Tübingen), G. Silling (Universitätsklinikum, Münster), G. Just-Nübling (Klinikum der Johann-Wolfgang-von-Goethe Universität, Frankfurt), C. Nerl (Städtisches Krankenhaus, Munich); Greece — M. Bakiri (Evangelismos Hospital, Athens), H. Giamarellou (Sismanogleion Hospital, Athens), G. Petrikkos (Laiko General Hospital, Athens); Hungary — M. Udvardy (University Medical School of Debrecen, Debrecen), E. Laszlo (National Institute of Hematology and Immunology, Budapest); Israel — J. M. Rowe (Rambam Medical Center, Haifa); Italy — L. Pagano (Policlinico Gemelli, Rome), P. Martino (Policlinico Umberto I, Rome), A. DelFavero (University Perugia Policlinico Monteluce, Perugia), G. Carosi (Spedali Civili, Brescia), G. Fioritoni (Ospedale Civile S. Spirito, Pescara), A.M. Nosari (Ospedale Niguarda, Milano), T. Barbui (Ospedali Riuniti di Bergamo, Bergamo); Mexico — J. Delgado (Centro Médico De Occidente, Guadalajara), C. Martinez (Antiguo Hospital Civil de Guadalajara, Guadalajara); New Zealand — R. Spearing (Christchurch Hospital, Christchurch); Peru — F. Salas (Hospital Nacional Guillermo Almenara Irigoyen, Lima), C. Carracedo (Instituto Nacional de Enfermedades Neoplasticas, Lima); Poland — T. Robak (Medical Academy, Lodz), W. Jedrzejczak (Medical Academy, Warsaw), A. Hellmann (Medical Academy, Gdansk), L. Konopka (Institute of Hematology and Transfusiology, Warsaw); South Africa — C.F. Slabber (Pretoria Academic Hospital, Pretoria), D. Brittain (Sandton Oncology Centre, Johannesburg, Gauteng); Spain — J. M. Fernández-Rañada (Hospital La Princesa, Madrid), F. Hernández-Navarro (Hospital La Paz, Madrid), J. Díaz-Mediavilla (Hospital Clínico San Carlos, Madrid), J. Tomás-Martinez (Fundación Jimenez Díaz, Madrid), J. Baro-Calle (Hospital Marques de Valdecilla, Santander), M. Rovira-Tarrats (Hospital Clínic i Provincial, Barcelona), J. Julia-Font (Hospital Vall d'Hebron, Barcelona), J. Belsaduch-Vidal (Hospital Son Dureta, Palma de Mallorca), C. Solano-Vercet (Hospital Clínico Universitario, Valencia), M.A. Sanz-Alonso (Hospital Universitario La Fe, Valencia), L. Vázquez (Hospital Clínico Universitario, Salamanca), J. Sierra-Gil (Hospital Sta.Creu i Sant Pau, Barcelona), M.N. Fernández (Clínica Puerta de Hierro, Madrid); Switzerland — T. Calandra (Centre Hospitalier Universitaire Vaudois, Lausanne), S. Zimmerli (Inselspital Bern, Bern); Taiwan — Y.-C. Chen (National Taiwan University Hospital, Taipei); Turkey — H. Akan (Ankara University Ibni Sinai Hospital, Ankara), O. Uzun (Hacettepe University Faculty of Medicine, Ankara); United Kingdom — G. Prentice (Royal Free Hospital, London), R. Chopra (Christie Hospital, Manchester); United States — R. Adam (University of Arizona College of Medicine, Tucson), A. Cross (University of Maryland Cancer Center, Baltimore), S. Ericson (Mary Babb Randolph Cancer Center, Morgantown, W. Va.), M. Goldman (Indiana University School of Medicine, Indianapolis), R. Greenberg (University of Kentucky, Lexington), J. Hiemenz (Walt Disney Memorial Cancer Institute, Orlando, Fla.), K. High (Wake Forest University School of Medicine, Winston-Salem, N.C.), V. Morrison (Veterans Affairs Medical Center, Minneapolis), P. Pappas (University of Alabama at Birmingham, Birmingham), F.B. Petersen (University of Utah, Salt Lake City), I. Raad (M.D. Anderson Cancer Center, Houston), A. Reboli (Cooper Hospital, University Medical Center, Camden, N.J.), J. Reinhardt (Christiana Care Health Services Research Institute, Newark, Del.), H. Schrager (Roger Williams Medical Center, Providence, R.I.), M. Schuster (University of Pennsylvania, Philadelphia), K. Sepkowitz (Memorial Sloan-Kettering Cancer Center, New York), Z. Temesgen (St. Mary's Hospital, Rochester, Minn.), H. Erba (University of Michigan, Ann Arbor), J. Greene (Moffitt Cancer Center, Tampa, Fla.), S. Filler (Harbor–UCLA Research and Education Institute, Torrance, Calif.), J. Wingard (University of Florida, Gainesville), J. Perfect (Duke University Medical Center, Durham, N.C.), P. Arnow (University of Chicago, Chicago), D. McKinsey (Infectious Disease Associates of Kansas City, Kansas City, Mo.), R. Betts (University of Rochester, Rochester, N.Y.), S. Chapman (University of Mississippi Medical Center, Jackson), J. Serody (Lineberger Cancer Center School of Medicine, Chapel Hill, N.C.), R. Fetchick (San Antonio Infectious Disease Consultants, San Antonio, Tex.), K. Mullane (Loyola University Health System, Maywood, Ill.), B. Segal (Roswell Park Cancer Institute, Buffalo, N.Y.); and Venezuela — H. Marcano (Hospital Universitario de Caracas – Servicio de Medicina I, Caracas).
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Related Letters:
Caspofungin versus Liposomal Amphotericin B for Empirical Therapy
Kontoyiannis D. P., Lewis R. E., Tattevin P., Bareau B., Camus C., Marty F. M., Lowry C. M., Schneemann M., Imhof A., Danaher P. J., Jones B. L., McLintock L. A., Walsh T. J., Donowitz G. R., dePauw B. E.
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N Engl J Med 2005;
352:410-414, Jan 27, 2005.
Correspondence
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